DESCRIPTION (from applicant's abstract): The goal of this research is to develop mechanism-based selective therapy for the treatment of HNSCC. Hypotheses: 1) Delineation of mechanism(s) of actions of ZD1694 should provide the basis for the design of mechanism-based drug sequence for optimal therapeutic benefit. 2) Higher therapeutic index and cure rate can be achieved with ZD1694 and CPT-11 used in sequence than in combination. Cell lines representing poorly differentiated SCC of the pharynx (FaDu) and a well-differentiated epidermoid carcinoma of the neck (A253), will be utilized to carry out the studies outlined. Specific Aims: 1) Verify that mechanisms associated with in vitro cytotoxicity to ZD1694 and the synergistic interaction between ZD1694 and SN38, an active metabolite of CPT-11, are predictive for in vivo therapeutic selectivity. 2) Evaluate the effect of circulating thymidine on the mechanism of action of ZD1694. 3) Establish that the synergistic interaction achieved in vitro between ZD1694 and SN38 are paralleled by sequential combinations with higher therapeutic index and cure rate. The proposed studies are expected to provide a rational basis for the design of clinical protocols in head and neck cancer.